7. Project Summary/Abstract The overarching goal of this program is to facilitate the discovery and preparation of complex, biologically active small molecules by devising novel chemical reactions and elucidating new principles of catalysis in the field of transition metal-catalyzed cross coupling. Our laboratory's early work demonstrated that oxidative addition of Ni to iminium or oxocarbenium ion intermediates offers a novel entry to C(sp3)?C cross coupling. This strategy leverages the modularity of cross-coupling catalysis to deliver new bond-forming reactions with classic reactive intermediates in organic synthesis. Recently, we and others recognized that Ni catalysis presents a powerful opportunity to functionalize another class of reactive intermediate in organic synthesis: carbon-centered radicals. In the current proposal, we advance this concept, building on strong preliminary data, to develop fundamentally new bond-forming reactions under exceptionally mild conditions. An example is the development of a unified platform for the enantioselective synthesis of ?- and ?-substituted amines and ethers, some of the most ubiquitous scaffolds in medicinal chemistry, via Ni-catalyzed coupling with radicals derived from acetals, aziridines, and iminium ions accessed via condensation of an amine and carbonyl derivative. Such transformations are uniquely suited to late-stage diversification under mild conditions and address many challenges and limitations of ether and amine synthesis by C?O/N bond formation. Our group has also established a new paradigm for catalytic C(sp3)?H functionalization that uses photocatalysis to deliver free radical species from C(sp3)?H bonds, and Ni catalysis to functionalize these radicals. This strategy offers numerous opportunities for late-stage C(sp3)?C bond formation that complement current approaches to C?H functionalization in selectivity and scope. We describe plans to advance these reaction platforms in terms of scope of coupling partners, catalyst control of regio- and stereoselectivity, and amenability to late-stage derivatization of natural products and medicinal compounds. Critical to our success will be the development and study of three ligand classes for Ni: phosphines featuring remote steric hindrance, bioxazolines, and electron-deficient olefins. Since most effort in the field of Ni catalysis has focused on reaction discovery, we expect that the development of ligands designed specifically for Ni will play a crucial role in advancing the capabilities of this field. Similarly, we will build on our lab's prior mechanistic work with the goal of developing predictive models for the reactivity of Ni with radicals and understanding the photochemistry and photophysics of Ni that could lay the foundation for advances in numerous fields.